The present invention is directed to compounds and their pharmaceutically acceptable salts, which inhibit matrix metalloproteinases, and are therefore useful in the treatment of mammals having disease-states alleviated by the inhibition of such matrix metalloproteinases.
Matrix metalloproteinases (xe2x80x9cMMPs)xe2x80x9d are a family of proteinases (enzymes) involved in the degradation and remodeling of connective tissues. Members of this family of endopeptidase enzymes are present in various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. These ubiquitous extracellular matrix components are present in the linings of joints, interstitial connective tissues, basement membranes, and cartilage. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, includingrheumatoid arthritis, osteoarthritis, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal ulceration, and in complications of diabetes. Another disorder wherein MMPs play a major role is in chronic wounds. Chronic wounds that are refractive to normal healing processes are characterized by an increase in the activity of matrix metalloproteinases. MMP inhibition is, therefore, recognized as a good target for therapeutic intervention.
In normal tissues, cellular connective tissue synthesis is offset by extracellular matrix degradation, the two opposing effects existing in dynamic equilibrium. Degradation of the matrix is brought about by the action of MMPs released from resident connective tissue cells and invading inflammatory cells. Normally these catabolic enzymes are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity, the latter through the action of specific regulators, such as TIMPs (tissue inhibitors of metalloproteinases), which form inactive complexes with MMPs, and more general proteinase regulators which form complexes with MMPs. These complexes prevent MMP action. Cellular level control of MMP activity occurs primarily by regulating MMP gene expression and by down regulating the expression of the membrane bound MMPs (MT-MMP) that activate the excreted proenzyme form of the MMP.
TIMPs can provide useful treatments for diseases associated with the excessive degradation of extracellular matrix, such as arthritic diseases (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, periodontal disease, corneal ulceration, ulceration of the skin, tumor invasion and metastasis, and aberrant angiogenesis.
TIMPs are glycoproteins and specifically regulate interstitial collagenases, typically on a 1:1 stoichiometric basis. That is, TIMPs form very specific regulatory complexes with the MMPs, only regulating a specific subset of the MMPs. In chronic wounds, the ratio of MMP to TIMP is high, such that most of the MMPs are unregulated. In fact, with elevated proteinase levels, the TIMP molecules themselves can be hydrolyzed. But there is no naturally occurring TIMP molecule that singly regulates all types of MMPs.
Many disorders are a result of uncontrolled breakdown of connective tissues by MMPs. These problems include, for example, rheumatoid arthritis; osteoarthritis; osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration; tumour metastasis, invasion and growth; neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis; and angiogenesis dependent diseases, which include angiofibromas, hemangioma, solid tumors, leukemia, metastasis, telangiectasia psoriasis scleroderma, pyogenic granuloma, Myocardial angiogenesis, plaque neovascularization, cororany collaterals, ischemic limb angiogenesis, corneal diseases, rubeosis, neovascular glaucoma, diabetic retinopathy, retrolental fibroplasia, arthritis, diabetic neovascularization, macular degeneration, wound healing, peptic ulcer, fractures, keloids, vasculogenesis, hematopoiesis, ovulation, menstruation, and placentation. Another major disorder that results from abnormal regulation of MMPs is chronic wounds.
One major reason that chronic wounds do not heal is that MMPs destroy the newly formed wound bed. However, the accelerated, uncontrolled breakdown of connective tissues by MMP catalysed resorption of the ECM is a feature of acute or chronic non-healing skin wounds. Many individuals suffer from these types of wounds. Open cutaneous wounds represent one major category of such wounds and include burn wounds, neuropathic ulcers, pressure sores, venous stasis ulcers, and diabetic ulcers. Worldwide, eight million people have chronic leg ulcers and seven million people have pressure sores (Clinica 559, 14-17, 1993). In the U.S. alone, the prevalence of skin ulcers is 4.5 million, including two million pressure sore patients, 900,000 venous ulcer patients and 1.6 million diabetic ulcer patients (Med Pro Month, June 1992, 91-94). The cost involved in treating these wounds is staggering and, at an average of $3,000 per patient, reaches over $13 billion per year for the U.S. alone.
Burn wounds have a reported incidence of 7.8 million cases per year worldwide, 0.8 million of which need hospitalization (Clinica 559). In the U.S., there are 2.5 million burn patients per year, 100,000 of which need hospitalization and 20,000 of which have burns involving more than 20% of the total body surface area (MedPro Month, June 1992).
Thus, there is a need in the art for improved regulation of MMPs to promote healing of chronic and acute wounds. It is necessary to have an inhibitor with relatively good affinity yet which is selective so not to be toxic to the cells. Furthermore, there is a need in the art to control overactive MMPs.
The invention provides new compounds which are useful as inhibitors of matrix metalloproteinases and which are effective in treating disease-states characterized by excessive activity of matrix metalloproteinases. Accordingly, one aspect of the invention is directed to 4,5-dihydroxyanthaquinone-2-carboxylic acid (AQCA) and derivatives thereof. 4,5-dihydroxyanthaquinone-2-carboxylic acid has the following formula: 
As one embodiment of the present invention, it has been found that AQCA is an inhibitor of matrix metalloproteinases. In addition, derivatives of AQCA have been found to be highly effective inhibitors of metalloproteinases. For example, modification at the 2 position of the AQCA yields a wide variety of effective matrix metalloproteinase inhibitors. Thus, the present invention comprises the use of AQCA as a matrix metalloproteinase and also comprises AQCA molecules that have been modified at the 2 position. A preferred method of modifying the AQCA molecule is by addition to the carboxyl group at the 2 position.
The AQCA molecule and the derivatives of the AQCA molecules are effective matrix metalloproteinase inhibitors and can be used as a therapeutic agent for those disorders wherein metalloproteinases are a factor in the etiology of the disorder. For example, the use of the present invention in treating wounds is particularly useful. The matrix metalloproteinase of the present invention can be administered by topical, transdermal, oral, rectal or parenteral (e.g., intravenous, subcutaneous or intramuscular) route.
These and other features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.